17-43094135-G-C

Position:

• chr17-43094135-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_007294.4(BRCA1):​c.1396C>G​(p.Arg466Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 0.776

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1396C>G	p.Arg466Gly	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1396C>G	p.Arg466Gly	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461768 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Arg466Gly variant was identified in 1 of 80 proband chromosomes (frequency: 0.01) from Moroccan individuals or families with early onset and familial breast/ovarian cancer (Tazzite_2012_22425665). Results of two evolutionary models predicting the significance of specific sites in BRCA1 exon 11 were conflicting, 1 study finding the variant had a functional effect and the other finding it did not have a functional effect (Burk-Herrick_2005_16518693, Fleming_2003_12531920). The variant was also identified in dbSNP (ID: rs80356964) “With Uncertain significance,other allele”, ClinVar (classified uncertain significance by Counsyl, Ambry Genetics and BIC; and classification not provided by Invitae), Clinvitae (1x), LOVD 3.0 (1x), and BIC Database (1x, with unknown clinical importance, classification pending). The variant was not identified in UMD (unavailable), MutDB, GeneInsight-COGR, Cosmic, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg466 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Gly to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	a variant of uncertain significance in the BRCA1 gene (p.Arg466Gly). The p.R466G variant (also known as c.1396C>G), located in coding exon 10 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1396. The arginine at codon 466 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in Moroccan and Saudi Arabian high-risk breast cancer cohorts (Tazzite A et al. Gynecol. Oncol. 2012 Jun;125:687-92; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). This amino acid position is poorly conserved in available vertebrate species. In-silico analysis showed conflicting results. ClinVar has an entry for this variant with 6 submissions, two stars, and no conflict. This variant is not found in gnomAD genomes. Currently, the pathogenicity of this variant is not clear. Therefore, it is classified as variant of uncertain significance. Pathogenic/likely pathogenic mutations cause hereditary breast/ovarian cancer syndrome (HBOS). -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2017	Variant summary: The BRCA1 c.1396C>G (p.Arg466Gly) variant located in the serine-rich domain (via InterPro) involves the alteration of a non-conserved nucleotide, which 4/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was absent in 121376 control chromosomes (ExAC). A publication cites the variant in an affected individual with limited information (ie, no cosegregation information). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer, in one patient co-occurring with a BRCA1 pathogenic variant (Tazzite et al., 2012; Abulkhair et al., 2018; Lerner-Ellis et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1515C>G; This variant is associated with the following publications: (PMID: 16518693, 31131967, 12531920, 22425665, 30199306, 15343273, 29884841, 32377563, 31911673, 32885271) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2023	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 30199306 (2018), 22425665 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2022	The p.R466G variant (also known as c.1396C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1396. The arginine at codon 466 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in Moroccan and Saudi Arabian high-risk breast cancer cohorts (Tazzite A et al. Gynecol. Oncol. 2012 Jun;125:687-92; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 08, 2023	This missense variant replaces arginine with glycine at codon 466 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 22425665, 30199306) and in a multifactorial analysis with likelihood ratios for pathogenicity based on co-occurrence with a pathogenic covariant and family history of 1.0673 and 0.9148, respectively (PMID: 31131967). This variant also has been reported in an individual affected with ovarian cancer that exhibited microsatellite instability and loss of MSH6 and the presence of a BRCA1 truncation variant in the last coding exon (PMID: 32885271). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 18, 2023

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 466 of the BRCA1 protein (p.Arg466Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 54240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.52	D;.;.;.;T;T;.;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.17	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.035	D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;.;D;.;D;D
Polyphen		0.77	P;.;.;B;.;.;.;.;.
Vest4		0.36
MutPred		0.55		Loss of loop (P = 0.0075);Loss of loop (P = 0.0075);.;Loss of loop (P = 0.0075);.;Loss of loop (P = 0.0075);.;.;Loss of loop (P = 0.0075);
MVP		0.73
MPC		0.31
ClinPred		0.63	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80356964; hg19: chr17-41246152;